Synthesis, Interaction With DNA/Bsa And Antiproliferative Activity Of Transition-Metal Complexes With Demethylcantharate And Pyridine (Benzothiazole) Derivatives

Demethylcantharidin (NCTD), derivative of cantharidin, not only possess intense antiproliferative activity in vitro and noteworthy inhibitory activity on protein serine/threonine phosphatases (PP1and PP2A), but also reduce the toxicity of cantharidin greatly. So we have designed and synthesized some novel transition-metal complexes with demethylcantharate and pyridine derivatives/benzothiazole. The interactions of these complexes with DNA and bovine serum albumin (BSA) were studied, and the interaction intensities and mode were obtained. Meanwhile, their antiproliferative activities were tested with MTT essay in vitro. The main work is as following:1. Four novel complexes (Hapy)2[M(DCA)2]-6H2O (M=Mn(Ⅱ)(1), Co(Ⅱ)(2), Ni(Ⅱ)(3), Cu(II)(4); DCA=demethylcantharate; Hapy=protonated2-aminopyridine) were synthesised and characterized by elemental analysis, molar conductance, infrared spectra and thermogravimetric analysis. Their structures were determined by X-ray diffraction, the complexes crystallized in the triclinic crystal system with Pi space group. DNA binding properties of the complexes were investigated via electronic absorption spectra, fluorescence spectra and viscosity measurements. The interaction with bovine serum albumin (BSA) was studied by fluorescence spectra. The antiproliferative activities of the complexes against human hepatoma cells (SMMC7721) and gastric cancer cells (MGC80-3) were tested with MTT assay in vitro. All the results showed that the complexes bind to DNA moderately via partial intercalation mode, and the complex4possessed the strongest binding ability. The complexes could quench the fluorescence of BSA strongly through static quenching from the formation of a ground-state complex between the fiuorophore and quencher, and the interacting intensity of complex3was stronger than other complexes. The antiproliferative activities of the complexes against the two cells were more intense than Na2(DCA), complex4had the strongest activity on human hepatoma cells and complex3possessed the most intense active on human gastric cancer cells.2. Five novel transition metal complexes [Mn2(DCA)2(bipy)2]·5H2O (5),[Co(DCA)(bipy)(H2O)](6),[Ni2(DCA)2(bipy)2(H2O)]·10H2O (7),[Zn2(DCA)2(bipy)2(H2O)]·10H2O (8) and [Cd2(DCA)2(bipy)2(H2O)2](9)(DCA=demethylcantharate; bipy=2,2’-bipyridine) were synthesized using metal acetates, demethylcantharidin (NCTD) and2,2’-bipyridine (bipy). The complexes were characterized by elemental analysis, molar conductance, infrared spectra and X-ray diffraction. The DNA binding properties of the complexes were studied by electronic absorption spectra, viscosity measurements and agarose gel electrophoresis. The interaction with bovine serum albumin (BSA) was investigated by fluorescence spectra. The antiproliferative activities of the complexes5-8against human hepatoma cells (SMMC7721) and gastric cancer cells (MGC80-3) were tested with MTT assay in vitro. The results showed the complexes bind to DNA via partial intercalation modes, and complexes6and7could cleave plasmid DNA through redox mechanism. The complexes could quench the fluorescence of BSA strongly through static quenching, complex6had the most intense binding ability, and the hydrophobicity of microenvironment around tryptophan residues in BSA changed. Meanwhile, complexes5,7and8had stronger antiproliferative effect than Na2(DCA) against the two cancer cells in the tested concentration range, complex8had the strongest activity on human hepatoma cells, complexes5and8possessed the most intense active on human gastric cancer cells.3. Four novel transition metal complexes of demethylcantharate (DCA) and2-aminobenzothiazole (abtz) were synthesized and characterized by elemental analysis, molar conductance, infrared spectra, thermogravimetric analysis and X-ray diffraction. Their structures were (Habtz)2[M(DCA)2]-6H2O (M=Ni(II)(10), Cu(II)(11), Zn(II)(12), Cd(II)(13); Habtz=protonated2-aminobenzothiazole), and they crystallized in the triclinic crystal system with P1space group. DNA binding properties of the complexes were investigated via electronic absorption spectra, fluorescence spectra, viscosity measurements and agarose gel electrophoresis; the interaction with bovine serum albumin (BSA) was studied by fluorescence spectra; the antiproliferative activities of the complexes10-12against human hepatoma cells (SMMC7721) and gastric cancer cells (MGC80-3) were tested with MTT assay in vitro. All the results showed that the complexes bind DNA through partial intercalation mode, and the complex11had the most intense binding ability; complexes11could cleave plasmid DNA radical mechanism; the complexes could quench the fluorescence of BSA strongly through static quenching, and complex10possessed the strongest interaction strength; the antiproliferative activities of the complexes against the two cells were more intense than Na2(DCA), complex12had the strongest activity on human hepatoma cells and complex11possessed the most intense active on human gastric cancer cells.